title: DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control.
abstract: BACKGROUND
  The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage.
  
  
  RESULTS
  We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53.
  
  
  CONCLUSIONS
  Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
authors.affiliation: Center for Quantitative Systems Biology and Department of Physics, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Siting
authors.initials: S
authors.lastname: Gan
authors.forename: Huaji
authors.initials: H
authors.lastname: Guan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Jue
authors.initials: J
authors.lastname: Shi
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2